1. Field of the Invention
This invention relates to the use of adenosine triphosphate (ATP) and, more particularly, to novel systems and methods for administration of ATP for the enhancement of muscle mass and/or strength.
2. The Background
The biological importance of adenosine triphosphate (ATP) first became apparent with the discovery of ATP in muscle tissue infusions by Fiske and Lohmann et al. in 1929. A. Szent-Gyorgi took the next logical step by demonstrating that ATP played an important role in muscle contraction. His experiments involved the addition of ATP to muscle fibers and then observing the subsequent contractions. Various researchers and those skilled in the art have progressively elucidated the role of ATP in muscle function since then. From these beginnings came the understanding and appreciation that ATP is the essential energy production molecule for every cell in the body. Similar phosphate-rich compounds are also found in every organism with ATP related compounds supplying all cellular energy. In 1982, Chaudry at the Yale Medical School published results showing that ATP was present in intracellular and interstitial fluids, thereby suggesting ATP's greatly expanded biological importance.
ATP and its breakdown product adenosine are also inherently involved in a number of extracellular processes like that of muscle contraction as described above. For example, some of the extracellular processes involving ATP may include neurotransmission, cardiac function (e.g., cardiac output, stroke volume, heart rate), platelet function, vasodilatation, perfusion (e.g., arterial pressure, cardiac output, total peripheral resistance), and liver glycogen metabolism.
As can be appreciated, these additional biological roles have given rise to various clinical applications of ATP and adenosine. For example, clinical applications may include applications of ATP and adenosine as aneuropathic and ischemic anaesthesia, ahypotensive agent for trauma or disease induced hypertension such as pulmonary hypertension, a mild hypoglycemic in type II diabetes, and at least preliminary evidence that ATP may be useful as an adjunctive therapy for radiation cancer treatment.
ATP and related compounds have been researched extensively for possible drug uses (see, Daly, J. Med. Chem., 25:197, (1982)). The most widespread of these clinical applications is in various cardiac treatments including the prevention of reperfusion injury after cardiac ischemia or stroke, the treatment of hypertension (see, Jacobson, et al., J. Med. Chem., 35, 407-422 (1992)), as well as the treatment of paroxysmal supra ventricular tachycardia (see, Pantely, et al., Circulation, 82, 1854 (1990)).
With regards to human performance specifically, the splitting of ATP to form adenosine diphosphate (ADP) is of critical importance in the functioning of muscle, since this is the reaction that directly supplies energy to myosin and actin to facilitate normal muscular contraction. In many cases, this requirement is met by the actual rebuilding of ATP as it is used, rather than by storing a very large amount of ATP in the muscle. However, under exceptionally demanding conditions, such as peak athletic performance or certain deficiency states induced by either inadequate nutrition or various diseases, ATP availability could prove to be a limiting step in actuating peak muscle output.
While therapeutic uses of ATP in various disease states is quite common, applications of ATP relating to possible benefits such as increased athletic performance in normal, healthy individuals appear to be largely absent in the published literature.
A method of increasing intracellular ATP through orally administered precursors of adenosine triphosphate in dietary supplements for treatment of reduced energy availability resulting from strenuous physical activity, illness, or trauma appears to be disclosed in U.S. Pat. No. 6,159,942. However, ATP itself is not administered; rather pentose sugars are administered individually, mixed into dry food or in solution. Specifically, the preferred pentose is D-ribose, singly or combined with creatine, pyruvate, L-carnitine, and/or vasodilating agents.
As appreciated by those skilled in the art, the mechanism of action for ribose to stimulate ATP production is through the phosphorylation of nucleotide precursors that may be present in the tissues. These are converted to adenosine monophosphate (AMP) and further phosphorylated to ATP. Adenosine is directly phosphorylated to AMP, while xanthine and inosine are first ribosylated by 5-phosphoribosyl-1-pyrophosphate (PRPP) and then converted to AMP. In the de novo synthetic pathway, ribose is phosphorylated to PRPP, and condensed with adenine to form the intermediate AMP. AMP is further phosphorylated via high energy bonds to form adenosine diphosphate (ADP) and ATP.
In certain circumstances, ATP can cross directly into the cell without the need for intracellular de novo synthesis. Chaudry (1982) explained that exogenous ATP crosses cellular membranes when depletion occurs within myosin units. ATP or ATP substrates may access human physiology orally, sublingually, or intravenously. Carbohydrates, oral ATP, or oral-sublingual ATP may be consumed for enhancing endurance performance and for preventing muscle exertion or heat stress cramps. Therefore, methods of delivering actual ATP to the bloodstream and subsequently to interstitial fluids may have benefits not associated with mere ATP precursors.
In addition to exhibiting the proper therapeutic effect, any method for delivering actual ATP to muscle cells in an attempt to prevent depletion must also include a consideration of the realities of the practical administration of a therapeutic agent in a daily athletic environment. First, the therapeutic agent must be suitable for sale as a dietary supplement, and/or functional food and not only as a drug. This requires that the therapeutic agent have certain technical and economic characteristics related to the dietary supplement and/or functional food industries. From a technical standpoint, the therapeutic agent should preferably be orally administered and suitable for inclusion in a variety of dosage forms such as tablets or capsules or may be included in-solid foods mixed into dry food or in solution. Additionally, the therapeutic agent should also be well tolerated vis a vis digestion and suitably stable both ex vivo and in vivo. From an economic standpoint, a therapeutic agent should ideally be robust enough for combination with a variety of other ingredients without the need for special handling during manufacture or special processing, packaging, or storing of the resulting composition or mixture.
ATP is generally known to be subject to degradation from exposure to high temperature and/or high humidity conditions and in the presence of a low pH, such as that found in stomach acid. It is therefore desirable to protect administered ATP from degradation by stomach acid through the use of a low. pH insoluble compound, such as a protective enteric coating. Sublingual ATP preparations, which are not generally subject to exposure to gastric fluids, exist but they are not typically suitable for inclusion in a variety of dosage forms and complex formulations. This creates the need to coat supplements containing currently available ATP (such as adenosine-5′-triphosphate disodium) to impart protective enteric properties after the final dosage form is manufactured.
While the technique of enteric coating has been applied to finished ATP dosage forms such as capsules and tablets, it has not been applied to bulk ATP preparations suitable for inclusion in alternate dosage forms common to nutritional supplements and/or functional food products such as liquids, nutrition bars, and powders, as well as, the above-mentioned tablets and capsules.
Consistent with the foregoing, an ideal ATP preparation should include protective enteric properties independent of the final dosage form, thus eliminating the need for potential customers to impart enteric protection during manufacture since this capability is both expensive and uncommon. And, additionally providing enteric protection for finished food dosage forms such as liquids, bars, and powders is not presently possible.